Identification and expression of multidrug resistancerelated ABC transporter genes in Candida krusei
Abstract
Infections with Candida krusei have increased in recent years as a consequence of its intrinsic resistance to fluconazole, an antifungal azole widely used in immunocompromised individuals to suppress infections due to azole-susceptible C. albicans. One established mechanism for azole resistance is drug efflux by ATP binding cassette (ABC) transporters. Since these transporters recognize structurally diverse drugs, their overexpression can lead to multidrug resistance (MDR). To identify C. krusei genes potentially involved in azole resistance, PCR was performed with primers corresponding to conserved sequences of MDR-related ABC transporters from other fungi. Two genes, ABC1 and ABC2, were identified; Southern blots suggested that both have one or two related gene copies in the C. krusei genome. ABC1 RNA was constitutively expressed at low levels in log phase cells while ABC2 RNA was undetectable. However, both genes were upregulated as cultures approached stationary phase, and this upregulation was correlated with decreased susceptibility to the lethal activity of the azole derivative miconazole. Furthermore, ABC1 was upregulated following brief treatment of C. krusei with miconazole and clotrimazole (but not other azoles), and the unrelated compounds albendazole and cycloheximide. The latter two compounds antagonized fluconazole activity versus C. krusei, supporting a role for the ABC1 transporter in azole efflux. Finally, miconazole-resistant mutants selected in vitro demonstrated increased constitutive expression of ABC1. Based on these expression data, genetic and functional characterization of the ABC1 transporter to directly test its role in C. krusei azole resistance would appear to be warranted.
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Other transporter genes are upregulated in azole-resistant C. glabrata, C. dubliniensis, C. krusei, and C. tropicalis.
“Other transporter genes have been reported to be upregulated in azole-resistant C. glabrata (CgCDR1, CgCDR2 (formerly named PDH1) and CgSNQ2 (another ABC transporter)) [100–102], C. dubliniensis (CdCDR1 and CdCDR2) [103], C. krusei (ABC1 and 2) [104, 105], and C. tropicalis (CDR1-homologue) isolates [44].”
From <i>Candida</i>Infections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [105]
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- Authors
- Katiyar, S. K., & Edlind, T. D.
- Affiliations
- Hahnemann University Hospital (US)
- ORCID
- Katiyar, S. K.
- Venue
- Medical Mycology
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-01
- Volume
- 39
- Issue
- 1
- Pages
- 109-116
- ISSN
- 0268-1218 (ISSN-L)
- 1369-3786
- 1460-2709
- OpenAlex
- W1991136405
- Cited by
- 104
- References
- 24
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 3 · 2018: 9 · 2017: 5 · 2016: 1 · 2015: 5 · 2014: 4 · 2013: 1 · 2012: 5
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Medical Mycology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7r01ai032433-08, 5r01ai046768-04)
- National Institute of Allergy and Infectious Diseases (AI-32433, AI46768)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Candida krusei, multidrug resistance, ABC transporters, azole resistance, fluconazole, miconazole, drug efflux, gene expression, clotrimazole, albendazole, cycloheximide, antifungal resistance
- MeSH terms
- Amino Acid Sequence, Antifungal Agents, Candida, Drug Resistance, Microbial, Genes, Fungal, Molecular Sequence Data, Phylogeny, Transcription, Genetic, Fluconazole, Gene Expression Regulation, Fungal, Sequence Alignment, ATP-Binding Cassette Transporters
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